Accrufer
ferric maltol
Species
Dog
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Dog
“Twenty-eight-day repeat dose oral administration toxicity studies were conducted in dogs with initial ferric maltol doses of 0, 250, 500, and 1000 mg/kg.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Twenty-eight-day repeat dose oral administration toxicity studies were conducted in dogs with initial ferric maltol doses of 0, 250, 500, and 1000 mg/kg.”
Species: general tox
Dog (ferric maltol); maltol alone in mouse, rat and dog
“These include 6-month studies in mice (Report 79029) and rats (Report 79031) at doses of 0, 100, 200 or 400 mg/kg/day by dietary administration, and a 3-month study in dogs (Report 79032) at doses of 0, 100, 200 or 300 mg/kg/day by administration of capsules.”
Species: DART
Not conducted with ferric maltol; mouse and rat EFD with ferrous sulfate/ferric sodium pyrophosphate
“Embryo-fetal development studies have not been conducted with ferric maltol. Embryo-fetal development studies have been conducted in mice and rats treated with ferrous sulfate and ferric sodium pyrophosphate.”
Species: carcinogenicity
Maltol only: mouse (18-month) and rat (2-year); not conducted with ferric maltol
“Maltol The carcinogenic potential of maltol has been evaluated in long-term animal toxicity studies in two species: CD-1 mice and Sprague-Dawley rats. Maltol was not carcinogenic in a 18-month study in mice at doses up to 400 mg/kg (approximately 5.6 times the human daily dose).”
Surrogate used in
No surrogate molecule; carcinogenicity and DART relied on maltol and other iron salts
“Carcinogenicity studies have not been conducted with ferric maltol. Ferric maltol was mutagenic in vitro in bacterial reverse mutation (Ames) assays.”
Study lengthopen answer page →
Longest pivotal study
4 (28-day dog)
“Twenty-eight-day repeat dose oral administration toxicity studies were conducted in dogs with initial ferric maltol doses of 0, 250, 500, and 1000 mg/kg.”
Pivotal GLP studies
GLP 28-day oral (gavage then capsule) dog study with ferric maltol
“Study title/ number: Iron Maltol: 28 Day Oral (Gavage/Capsule) Sub-Chronic Toxicity Study in the Beagle/6148-148/40”
Route in tox
Oral (gavage days 1–5, then capsule)
“Route of administration: Oral gavage on days 1 through 5 then oral capsule from day 6 onward.”
Skipped studiesopen answer page →
Genotoxicity
Ferric maltol positive in Ames; maltol positive in Ames and in vivo mouse micronucleus assay
“Ferric maltol was mutagenic in vitro in bacterial reverse mutation (Ames) assays. Ferric maltol increased revertant frequency in the absence and presence of metabolic activation. Fertility studies have not been conducted with ferric maltol. Maltol was mutagenic in the Ames assay and increased micronuclei in an in vivo clastogenicity assay in mice.”
Carcinogenicity
Maltol (complex component) not carcinogenic in 18-month mouse and 2-year rat studies up to 400 mg/kg
“Maltol was not carcinogenic in a 18-month study in mice at doses up to 400 mg/kg (approximately 5.6 times the human daily dose). Maltol was not carcinogenic in a 2-year study in rats at doses up to 400 mg/kg (approximately 11.2 times the human daily dose).”
Reproductive & developmental
Maltol multigeneration rat study: no effects on mating, fertility or early embryonic development up to 400 mg/kg/day
“In a multi-generation animal reproduction study in male and female rats, there were no effects on mating, fertility, or early embryonic development at doses up to 400 mg/kg/day (approximately 11.2 times the human daily dose).”
Safety pharmacology
Not conducted; justified because the active moiety is iron
“No standalone safety pharmacology studies were conducted for ferric maltol, which is scientifically justified as the active moiety is iron.”
Genotox: Ames
Positive (ferric maltol and maltol), with and without metabolic activation
“Ferric maltol was mutagenic in vitro in bacterial reverse mutation (Ames) assays. Ferric maltol increased revertant frequency in the absence and presence of metabolic activation.”
Genotox: in vitro mammalian
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Genotox: in vivo
Maltol: positive mouse micronucleus at 774 mg/kg intraperitoneal
“Maltol was clastogenic in vivo in a mouse micronucleus assay (increase in polychromatic erythrocytes) at intraperitoneal doses of 774 mg/kg.”
Carcinogenicity model
Maltol: 18-month mouse and 2-year rat, not carcinogenic; none with ferric maltol
“Maltol was not carcinogenic in an 18-month study in mice at doses up to 400 mg/kg (approximately 5 times the human daily dose). Maltol was also not carcinogenic in a 2-year study in rats at doses up to 400 mg/kg (approximately 10 times the human daily dose).”
Carcinogenicity timing
None with ferric maltol; maltol 18-month mouse carcinogenicity study report submitted in the NDA
“The NDA contains a study report for a mouse 18-month carcinogenicity study of maltol at doses of 0, 100, 200 or 400 mg/kg/day by dietary administration (Report 75009).”
hERG / QT
Not conducted; no standalone safety pharmacology (active moiety is iron)
“No standalone safety pharmacology studies were conducted for ferric maltol, which is scientifically justified as the active moiety is iron.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Accrufer don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Dog: reduced food intake; raised platelets, ALP and bilirubin; increased liver, kidney, adrenal and thyroid weights; iron in liver and kidney cells (FDA multi-discipline review, p. 29)
NOAEL / key findings
Dog: reduced food intake; raised platelets, ALP and bilirubin; increased liver, kidney, adrenal and thyroid weights; iron in liver and kidney cells
“Test article-related toxicities included reduced food intake, increased platelet counts, alkaline phosphatase activity, and bilirubin concentrations. Liver, kidney, adrenals, and thyroid weights increased. Liver and kidney cells stained for the presence of iron.”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Rat: absorbed iron bound to transferrin; after IV dosing, highest iron levels in liver and bone marrow, protein-bound
“Radiolabeled iron from ferric maltol in the rat intraduodenal administration studies was found bound to transferrin with a time to half maximal concentration (T½) of 133 minutes. Ferric maltol as single 1000 µg or 1 mg IV doses of iron was administered to rats, resulting in highest iron concentrations in the liver and bone marrow, with the iron being bound to proteins.”
Modality-specific risk
Mutagenicity of ferric maltol and maltol in Ames assays
“Ferric maltol was mutagenic in vitro in bacterial reverse mutation (Ames) assays.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
No immunogenicity concerns
“There are no immunogenicity concerns with the drug product, ferric maltol or its components.”
Label warnings
- Increased Risk of Inflammatory Bowel Disease (IBD) Flare
- Iron Overload
- Risk of Overdosage in Children Due to Accidental Ingestion
Gastrointestinal
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Accrufer don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Dog: reduced food intake; raised platelets, ALP and bilirubin; increased liver, kidney, adrenal and thyroid weights; iron in liver and kidney cells (FDA multi-discipline review, p. 29)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
28-day oral dog study with ferric maltol; recovery phase not stated
“The general conclusions from these studies were that oral administration of maltol in the context of the maximum daily intake of the proposed drug product are not toxicologically significant or are not appreciably different than the results of the 28-day repeat dose toxicology study in dogs administered iron maltol described above.”
Pivotal GLP studies
GLP 28-day oral (gavage then capsule) dog study with ferric maltol
“Study title/ number: Iron Maltol: 28 Day Oral (Gavage/Capsule) Sub-Chronic Toxicity Study in the Beagle/6148-148/40”
DART package
Species: DART
Not conducted with ferric maltol; mouse and rat EFD with ferrous sulfate/ferric sodium pyrophosphate
“Embryo-fetal development studies have not been conducted with ferric maltol. Embryo-fetal development studies have been conducted in mice and rats treated with ferrous sulfate and ferric sodium pyrophosphate.”
Reproductive & developmental
Maltol multigeneration rat study: no effects on mating, fertility or early embryonic development up to 400 mg/kg/day
“In a multi-generation animal reproduction study in male and female rats, there were no effects on mating, fertility, or early embryonic development at doses up to 400 mg/kg/day (approximately 11.2 times the human daily dose).”
PPND / ePPND: when
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Carcinogenicity
Species: carcinogenicity
Maltol only: mouse (18-month) and rat (2-year); not conducted with ferric maltol
“Maltol The carcinogenic potential of maltol has been evaluated in long-term animal toxicity studies in two species: CD-1 mice and Sprague-Dawley rats. Maltol was not carcinogenic in a 18-month study in mice at doses up to 400 mg/kg (approximately 5.6 times the human daily dose).”
Carcinogenicity model
Maltol: 18-month mouse and 2-year rat, not carcinogenic; none with ferric maltol
“Maltol was not carcinogenic in an 18-month study in mice at doses up to 400 mg/kg (approximately 5 times the human daily dose). Maltol was also not carcinogenic in a 2-year study in rats at doses up to 400 mg/kg (approximately 10 times the human daily dose).”
Carcinogenicity timing
None with ferric maltol; maltol 18-month mouse carcinogenicity study report submitted in the NDA
“The NDA contains a study report for a mouse 18-month carcinogenicity study of maltol at doses of 0, 100, 200 or 400 mg/kg/day by dietary administration (Report 75009).”
Safety marginopen answer page →
Safety margin at NOAEL
Maltol rat EFD: no adverse effects at 6x recommended human dose (no repeat-dose margin stated)
“Oral administration of maltol to pregnant rats during organogenesis at doses 6 times the recommended human dose resulted in no adverse developmental outcomes.”
NOAEL / key findings
Dog: reduced food intake; raised platelets, ALP and bilirubin; increased liver, kidney, adrenal and thyroid weights; iron in liver and kidney cells
“Test article-related toxicities included reduced food intake, increased platelet counts, alkaline phosphatase activity, and bilirubin concentrations. Liver, kidney, adrenals, and thyroid weights increased. Liver and kidney cells stained for the presence of iron.”
Efficacy evidenceopen answer page →
Efficacy evidence
Radiolabeled iron studies in rats (confirmed in dogs): iron transferred to transferrin and ferritin; literature on iron
“Studies with radiolabeled iron in rats, confirmed in dogs and humans, demonstrate that intact ferric maltol is found in the gastrointestinal tract, but not in the blood.”
Why that model
Iron pharmacology extensively characterized in the literature
“The scientific literature includes an exhaustive characterization of the presence and pharmacological effects of iron in the human body.”
Reviewer's view of the efficacy data
FDA: nonclinical pharmacology/toxicology package adequate; no outstanding issues
“The nonclinical pharmacology/toxicology studies submitted to the NDA are adequate and there are no outstanding issues from a nonclinical perspective that would prevent approval of ferric maltol for the proposed indication.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies with ferric maltol; rodent carcinogenicity data on maltol relied on
Why: Maltol not carcinogenic in mice and rats; carcinogenic potential of ferric maltol under proposed use appears low · Weight of evidence
“Carcinogenicity studies have not been conducted with ferric maltol.”
“Based on the available information the carcinogenic potential of ferric maltol under the proposed use scenario appears low.”
DARTVerdict not stated
No embryo-fetal or fertility studies with ferric maltol; ferrous sulfate, ferric sodium pyrophosphate and maltol data used
“Embryo-fetal development studies have not been conducted with ferric maltol. Embryo-fetal development studies have been conducted in mice and rats treated with ferrous sulfate and ferric sodium pyrophosphate.”
Safety pharmacologyAcceptedBeyond the letter
No standalone safety pharmacology studies
Why: Active moiety is iron · Pharmacology or kinetics
“No standalone safety pharmacology studies were conducted for ferric maltol, which is scientifically justified as the active moiety is iron.”
GenotoxicityVerdict not stated
Ferric maltol positive in Ames; maltol positive in Ames and in vivo mouse micronucleus
“Ferric maltol was mutagenic in vitro in bacterial reverse mutation (Ames) assays. Ferric maltol increased revertant frequency in the absence and presence of metabolic activation.”
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